The Specific Aim of this proposal is to test the feasibility of using vagus nerve stimulation (VNS) as an adjunct to prolonged exposure therapy (PE) for treating PTSD patients who are refractory to PE. PE is the treatment of choice for such patients. However, PE is successful in as few as 50% of cases. Refractory PTSD patients have high rates of suicide, substance abuse and addiction, violent crimes, depression, and general loss of productivity. There is an urgent need to develop a therapy for patients with refractory PTSD. PE aims to reduce the conditioned fear response by training patients to develop new situation-appropriate responses. Treatment of patients with memory-enhancing drugs appears to be an effective adjunct to exposure therapy for a number of conditions, including PTSD. However, the number of studies is few and even in those studies there remains a significant number of refractory patients. Thus, the use of memory enhancing techniques appears promising; but more effective options are needed. We have found that VNS paired with training can greatly enhance neuroplasticity and rehabilitation (in sensory, motor, and limbic systems). These findings include the discovery that pairing VNS with extinction trials increases the rate of extinction in normal rats, a study that was supported by a successful Phase I SBIR that set the stage for the current proposal. We also demonstrated that VNS pairing with extinction training reverses fear conditioning-related synaptic changes in the rat brain, and collected preliminary data showing that we can produce a well-established rodent model of PTSD in our laboratory. We have a record of extending our positive VNS-pairing findings in pre-clinical animal models to clinically meaningful results in humans for tinnitus and stroke. Because these clinical findings were both predicted by our pre-clinical animal models, it is reasonable to test pairing VNS with PE to reverse the effects of conditioned fear in refractory PTSD patients, if animal studies support such a therapy. While we previously demonstrated positive effects in a rat model of fear conditioning, to test feasibility of moving our therapy forward in refractory patients, we will cary out a study in a model of refractory PTSD. To this end, we will use a rat model of PTSD in which rats are resistant (refractory) to extinction: Single Prolonged Stressor (SPS). Test of Feasibility The VNS group must show complete reversal of the fear response following extinction. The reversal in the VNS SPS group must be larger than any reversal in the Sham stimulated SPS group (P < 0.05). See Experimental section for more details. Phase II will use parametric studies for improving stimulation parameters while working with PTSD clinicians and PE therapists to develop the protocol to pair therapy with VNS.